NOTCH signaling in skeletal progenitors is critical for fracture repair

Fracture nonunions develop in 10%–20% of patients with fractures, resulting in prolonged disability. Current data suggest that bone union during fracture repair is achieved via proliferation and differentiation of skeletal progenitors within periosteal and soft tissues surrounding bone, while bone marrow stromal/stem cells (BMSCs) and other skeletal progenitors may also contribute. The NOTCH signaling pathway is a critical maintenance factor for BMSCs during skeletal development, although the precise role for NOTCH and the requisite nature of BMSCs following fracture is unknown. Here, we evaluated whether NOTCH and/or BMSCs are required for fracture repair by performing nonstabilized and stabilized fractures on NOTCH-deficient mice with targeted deletion of RBPjk in skeletal progenitors, maturing osteoblasts, and committed chondrocytes. We determined that removal of NOTCH signaling in BMSCs and subsequent depletion of this population result in fracture nonunion, as the fracture repair process was normal in animals harboring either osteoblast- or chondrocyte-specific deletion of RBPjk. Together, this work provides a genetic model of a fracture nonunion and demonstrates the requirement for NOTCH and BMSCs in fracture repair, irrespective of fracture stability and vascularity

Ceftazidime-avibactam induced renal disorders: past and present

With the increasing prevalence of multidrug-resistant Gram-negative bacterial pathogens worldwide, antimicrobial resistance has become a significant public health concern. Ceftazidime-avibactam (CAZ-AVI) exhibited excellent in vitro activity against many carbapenemase-producing pathogens, and was widely used for the treatment of various complicated infections. CAZ-AVI is well tolerated across all dosing regimens, and its associated acute kidney injury (AKI) in phase II/III clinical trials is rare. However, recent real-world studies have demonstrated that CAZ-AVI associated AKI was more frequent in real-world than in phase II and III clinical trials, particularly in patients receiving concomitant nephrotoxic agents, with critically ill patients being at a higher risk. Herein, we reviewed the safety data related to renal impairment of CAZ-AVI, and discussed its pharmacokinetic/pharmacodynamic targets and dosage adjustment in patients with impaired renal function. This review aimed to emphasize the importance for healthcare professionals to be aware of this adverse event of CAZ-AVI and provide practical insights into the dosage optimization in critically ill patients with renal dysfunction

De novo assembly and characterization of the complete chloroplast genome of Elymus magellanicus (É.Desv.) Á.Löve, 1984 (Poaceae, Pooideae)

Elymus magellanicus (É.Desv.) Á.Löve is a foliage accent plant that originated in South America. In this study, the complete chloroplast genome of E. magellanicus is reported. It was found to have a total size of 133,249 bp. The chloroplast genome was found to consist of two inverted repeats (IRA and IRB) of 21,421 bp each, a small single-copy region of 12,709 bp, and a large single-copy region (77,698 bp). The annotation results show the GC content of the chloroplast genome to be 38.47%, including 40 tRNA genes, 82 protein-coding genes, and 8 rRNA genes. Phylogenetic analysis of 29 species revealed that E. magellanicus is closely related to E. arenarius

Sirt1 protects against intervertebral disc degeneration induced by 1,25-dihydroxyvitamin D insufficiency in mice by inhibiting the NF-κB inflammatory pathway

Background: It has been demonstrated that vitamin D deficiency is associated with an increased risk of patients developing lumbar disc herniation. However, intervertebral disc degeneration caused by active vitamin D deficiency has not been reported. Thus, the purpose of this study was to e investigate the role and mechanism of 1,25-dihydroxyvitamin D (1,25(OH)2D) insufficiency in promoting intervertebral disc degeneration. Methods: The phenotypes of intervertebral discs were compared in wild-type mice and mice with heterozygous deletion of 1α-hydroxylase [1α(OH)ase+/−] at 8 mouths of age using iconography, histology and molecular biology. A mouse model that overexpressed Sirt1 in mesenchymal stem cells on a 1α(OH)ase+/− background (Sirt1Tg/1α(OH)ase+/−) was generated by crossing Prx1-Sirt1 transgenic mice with 1α(OH)ase+/− mice and comparing their intervertebral disc phenotypes with those of Sirt1Tg, 1α(OH)ase+/− and wild-type littermates at 8 months of age. A vitamin D receptor (VDR)-deficient cellular model was generated by knock-down of endogenous VDR using Ad-siVDR transfection into nucleus pulposus cells; VDR-deficient nucleus pulposus cells were then treated with or without resveratrol. The interactions between Sirt1 and acetylated p65, and p65 nuclear localization, were examined using co-immunoprecipitation, Western blots and immunofluorescence staining. VDR-deficient nucleus pulposus cells were also treated with 1,25(OH)2D3, or resveratrol or 1,25(OH)2D3 plus Ex527 (an inhibitor of Sirt1). Effects on Sirt1 expression, cell proliferation, cell senescence, extracellular matrix protein synthesis and degradation, nuclear factor-κB (NF-κB), and expression of inflammatory molecules, were examined, using immunofluorescence staining, Western blots and real-time RT-PCR. Results: 1,25(OH)2D insufficiency accelerated intervertebral disc degeneration by reducing extracellular matrix protein synthesis and enhancing extracellular matrix protein degradation with reduced Sirt1 expression in nucleus pulposus tissues. Overexpression of Sirt1 in MSCs protected against 1,25(OH)2D deficiency-induced intervertebral disc degeneration by decreasing acetylation and phosphorylation of p65 and inhibiting the NF-κB inflammatory pathway. VDR or resveratrol activated Sirt1 to deacetylate p65 and inhibit its nuclear translocation into nucleus pulposus cells. Knockdown of VDR decreased VDR expression and significantly reduced the proliferation and extracellular matrix protein synthesis of nucleus pulposus cells, significantly increased the senescence of nucleus pulposus cells and significantly downregulated Sirt1 expression, and upregulated matrix metallopeptidase 13 (MMP13), tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β) expression; the ratios of acetylated and phosphorylated p65/p65 in nucleus pulposus cells were also increased. Treatment of nucleus pulposus cells with VDR reduction using 1,25(OH)2D3 or resveratrol partially rescued the degeneration phenotypes, by up-regulating Sirt1 expression and inhibiting NF-κB inflammatory pathway; these effects in nucleus pulposus cells were blocked by inhibition of Sirt1. Conclusion: Results from this study indicate that the 1,25(OH)2D/VDR pathway can prevent the degeneration of nucleus pulposus cells by inhibiting the NF-κB inflammatory pathway mediated by Sirt1.The Translational Potential of This Article: This study provides new insights into the use of 1,25(OH)2D3 to prevent and treat intervertebral disc degeneration caused by vitamin D deficiency

Effect of White Mud as a Second Filler on the Mechanical and Thermal Properties of Bamboo Residue Fiber/Polyethylene Composites

The purpose of this study was to investigate the effect of white mud (WM) on mechanical and thermal properties of bamboo plastic composites (BPCs). Bamboo residue fibers (BRFs) and WM were added as the reinforcement, and high-density polyethylene (HDPE) served as the matrix. The lubricating agent and coupling agent were polyethylene wax and maleated polyethylene (MAPE), respectively. The mixture was used to manufacture BPCs using a twin-screw extruder. The crystal structure and thermal properties of BPCs were investigated by X-ray diffraction (XRD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). The results showed that the particle size of the WM was 700 nm to 50 μm, which are made mainly of calcium carbonate. BPCs with WM significantly increased the flexural and tensile properties, but the impact strength decreased because of the presence of WM. The flexural and tensile strength of composites with 18 wt% BPF were increased by 36.81% and 6.26%, respectively, while the flexural and tensile modulus were increased by 164.29% and 64.33%, respectively. XRD demonstrated the WM had little effect on the crystal structure of BPCs. Compared to BPCs without WM, the T5% of composites with 22 wt% WM decreased by 27.9 °C. As the WM content increased, the crystallinity of the BPCs decreased initially, then increased with increasing WM content

Structural insights into photosystem II supercomplex and trimeric FCP antennae of a centric diatom Cyclotella meneghiniana

Diatoms are dominant marine algae and contribute around a quarter of global primary productivity, the success of which is largely attributed to their photosynthetic capacity aided by specific fucoxanthin chlorophyll-binding proteins (FCPs) to enhance the blue-green light absorption under water. We purified a photosystem II (PSII)-FCPII supercomplex and a trimeric FCP from Cyclotella meneghiniana (Cm) and solved their structures by cryo-electron microscopy (cryo-EM). The structures reveal detailed organizations of monomeric, dimeric and trimeric FCP antennae, as well as distinct assemblies of Lhcx6_1 and dimeric FCPII-H in PSII core. Each Cm-PSII-FCPII monomer contains an Lhcx6_1, an FCP heterodimer and other three FCP monomers, which form an efficient pigment network for harvesting energy. More diadinoxanthins and diatoxanthins are found in FCPs, which may function to quench excess energy. The trimeric FCP contains more chlorophylls c and fucoxanthins. These diversified FCPs and PSII-FCPII provide a structural basis for efficient light energy harvesting, transfer, and dissipation in C. meneghiniana

Excitation dynamics and relaxation in the major antenna of a marine green alga Bryopsis corticulans

The light-harvesting complexes II (LHCIIs) of spinach and Bryopsis corticulans as a green alga are similar in structure, but differ in carotenoid (Car) and chlorophyll (Chl) compositions. Carbonyl Cars siphonein (Spn) and siphonaxanthin (Spx) bind to B. corticulans LHCII likely in the sites as a pair of lutein (Lut) molecules bind to spinach LHCII in the central domain. To understand the light-harvesting and photoprotective properties of the algal LHCII, we compared its excitation dynamics and relaxation to those of spinach LHCII been well documented. It was found that B. corticulans LHCII exhibited a substantially longer chlorophyll (Chl) fluorescence lifetime (4.9 ns vs 4.1 ns) and a 60% increase of the fluorescence quantum yield. Photoexcitation populated (3)Car* equally between Spn and Spx in B. corticulans LHCII, whereas predominantly at Lut620 in spinach LHCII. These results prove the functional differences of the LHCIIs with different Car pairs and Chl a/b ratios: B. corticulans LHCII shows the enhanced blue-green light absorption, the alleviated quenching of 1 Chl*, and the dual sites of quenching (3)Chl*, which may facilitate its light-harvesting and photoprotection functions. Moreover, for both types of LHCIIs, the triplet excitation profiles revealed the involvement of extra (3)Car* formation mechanisms besides the conventional Chl-to-Car triplet transfer, which are discussed in relation to the ultrafast processes of (1)Chl* quenching. Our experimental findings will be helpful in deepening the understanding of the light harvesting and photoprotection functions of B. corticulans living in the intertidal zone with dramatically changing light condition

Sequencing and characterization of the complete mitochondrial genome of Thinopyrum obtusiflorum (DC.) Banfi, 2018 (Poaceae)

In this study, the mitochondrial genome of Thinopyrum obtusiflorum was sequenced, assembled, and annotated. The complete circular mitogenome of Th. obtusiflorum is 390,725 bp in length and the overall A + T content of mitogenome is 55.61%. It harbors 33 protein-coding genes (PCGs), 21 transfer RNA genes (tRNAs), six ribosomal RNA genes (rRNAs), and 20 simple sequence repeats (SSRs). Phylogenetic analysis indicates that Th. obtusiflorum is a sister to the clade including Aegilops speltoides, Triticum aestivum, and Triticum aestivum cultivar Chinese Yumai in the Triticeae